Nitroanilides and their preparation

ABSTRACT

Novel aryloxy-nitroanilides of formula ##STR1## wherein R is alkyl from 1 to 5 carbon atoms or unsubstituted or substituted aryl of from 6 to 10 carbon atoms; one of R 1  and R 2  is a hydrogen atom and the other is aryloxy, wherein the aryl is unsubstituted or substituted with one or more alkyl of from 1 to 10 carbon atoms, with the proviso that when R is methyl, R 1  may not be unsubstituted phenoxy and when R is 2-hydroxy-5-chlorophenyl, R 2  may not be unsubstituted or chloro or methyl substituted phenoxy, and a method of preparing them. The compounds are suitable as intermediates for the preparation of anilines, required in the preparation of useful photographic and pharmaceutical compounds.

This invention relates to novel aryloxy-nitroanilides and a process forpreparing them.

Certain nitroanilides are suitable as intermediates which can be readilyconverted to their corresponding anilines, required in the preparationof useful photographic and pharmaceutical compounds. Previous methods ofpreparation have not been suitable for large scale synthesis of anilinesparticularly for those analogues which are ballasted. Selectivereduction of dinitro analogues as in Anales de Fisica y Quimica (1966),451, P. E Verkade and C. P. Van Dijk result in the formation of mixturesof isomers with consequent separation difficulties, whilst preparationof the required anilines from ethyl-4-chloro-3-nitrobenzoate is aprotracted and expensive procedure.

A method of preparing 2-phenoxy-5-nitrotroacetanilide in low yield isalready known (A. R. Fox and K. H. Pausacker, J Chem Soc. (1957),295-301) in which 2-chloro-5-nitroacetanilide is reacted with a largeexcess of sodium phenoxide under molten conditions and in the presenceof copper powder.

The present invention relates to a method of preparingaryloxy-nitroanilides which avoids this use of a large excess of phenol,is suitable for large scale synthesis end gives the anilides in goodyields, and to the novel intermediates thereof. The anilides can besubsequently hydrolysed to the required anilines using known methods.

According to the present invention there are provided novelintermediates of formula (I). ##STR2## wherein R is alkyl from 1 to 5carbon atoms or unsubstituted or substituted aryl of from 6 to 10 atoms,one of R¹ and R² is hydrogen and the other is aryloxy, wherein the arylis unsubstituted or substituted with one or more alkyl of from 1 to 10carbon atoms, with the proviso that when R is methyl, R¹ may not beunsubstituted phenoxy and when R is 2-hydroxy-5-chlorophenyl, R² may notbe unsubstituted or chloro or methyl substituted phenoxy.

As used herein and throughout the specification the term alkyl denotes astraight or branched chain alkyl group.

When R is a substituted aryl group, it may be substituted, for example,by one or more halo, alkyl, ester or sulfonyl-containing groups.However, preferred intermediates are those wherein R is a phenyl groupor most preferably a methyl group and especially those wherein one of R¹and R² is a substituted phenoxy group. Particularly preferred compoundsare

2-(4-t-octylphenoxy)-5-nitroacetanilide,

4-(4-t-octylphenoxy)-3-nitroacetanilide,

2'-(2,4-di-t-pentylphenoxy)-5'-nitrobenzanilide, and

2-(4-t-butylphenoxy)-5-nitrobenzanilide and

2-phenoxy-5-nitrobenzanilide.

In a further aspect of the present invention there is provided a methodof preparing intermediates of formula (I)' ##STR3## wherein R is alkylfrom 1 to 5 carbon atoms or unsubstituted or substituted aryl of from 6to 10 carbon atoms, one of R¹ and R² is hydrogen and the other is anaryloxy, wherein the aryl is unsubstituted or substituted with one ormore alkyl of from 1 to 10 carbon atoms, comprising the step of reactinga compound of formula (II) ##STR4## wherein R is as defined above andone of L¹ and L² is a hydrogen and the other is a leaving group, with acompound of formula R³ OH, wherein R³ is aryl as defined for R¹ and R².

Preferably the reaction is carried out in the presence of a base, suchas potassium carbonate or sodium hydride, and with a polar aproticsolvent, such as dimethylformamide or diglyme (bis-(2-methoxyethyl)ether, or a nonpolar hydrocarbon solvent, such as xylene. Although themost preferred solvent is dimethylformamide these other solvents workwell at elevated temperatures, especially at their boiling points.

The leaving group is preferably a halogen atom, especially chloro orfluoro, or a sulphonate group.

The most suitable reaction temperature will vary according to thereactants involved and in particular the leaving group. When R is methyland the leaving group is chloro, temperatures in excess of 140° C. areadvantageous, whilst the corresponding fluoro compound reacts moreeffectively at between room temperature to 100° C. When R is phenyl, useof room temperature minimises the formation of by-products.

An extension of the method of the invention is that2-fluoro-5-nitroaniline can also react at elevated temperatures with acompound R³ OH, preferably under basic conditions and with a polaraprotic solvent to give 2-aryloxy-5-nitroanilines.

The invention is illustrated by the following examples:

EXAMPLE 1 2-(4-t-Octylphenoxy)-5-nitroacetanilide [R=Me; R¹=4-t-octylphenoxy; R² =H]

A mixture of 2-chloro-5-nitroacetanilide (214 g, 1.0 mole),4-t-octylphenol (227 g, 1.1. mole), finely ground anhydrous potassiumcarbonate (207 g, 1.5 mole) and dimethylformamide (300 ml) was heatedand stirring begun when the mixture became sufficiently mobile at 60° C.At 140° C. an exotherm to 150° C. occurred and vigorous evolution ofcarbon dioxide commenced. The mixture was stirred at 150° C. for afurther 1.5 hours, after which time a t.l.c. showed very little startingmaterial. After cooling to 110° C., toluene (600 ml) was added and themixture washed with hot (50° C.) water (750 ml). The aqueous layer wasrun off and the toluene removed to give a dark red oil to which methanol(1000 ml) was added. After cooling to 0° C., the solid was collected,washed with ice cold methanol (4×100 ml) and dried to give the product(210 g). Partial evaporation of the liqours and cooling gave a secondcrop of product which was collected, washed with methanol (3×50 ml),dried and combined with the first crop to give a total yield of 262 g(68%). An analytically pure sample of the product melted at 140° C.

EXAMPLE 2 4-(4-t-Octylphenoxy)-3-nitroacetanilide [R=Me; R.sup. =H R²=4-t-octylphenoxy]

Using conditions similar to the above (reaction time, 3.5 hours),4-chloro-3-nitroacetanilide was reacted with 4-t-octylphenol to giveafter column chromatography (2:1 petrol:ethyl acetate) the product 27.0g (70%) as a pale orange solid m.p 121° C.

EXAMPLE 3 2'-(2,4-di-t-pentylphenoxy)-5'-nitrobenzanilide [R=Ph R¹=2,4-di-t-pentylphenoxy; R² =H]

2,4-di-t-pentylphenol (3.25 g, 13.9 mmole) was slowly added to 80%sodium hydride (0.42, 14 mmole) in dry dimethylformamide (10 ml). Afterhydrogen evolution had ceased, solid 2-fluoro-5-nitrobenzanilide (3.2 g,12.3 mmole) was added and the deep red reaction mixture stirred at roomtemperature for four days. The mixture was poured into water andextracted with ethyl acetate. The combined organic extracts were washedsuccessively with water and saturated sodium bicarbonate solution andthen dried over sodium sulphate. Removal of the solvent gave an oilwhich on crystallization from n-hexane gave the product as a solid 3.84g (70%) m.p 123° C.

EXAMPLE 4 2-(4-t-butylphenoxy)-5-nitrobenzanilide [R =Ph; R¹=4-t-butylphenoxy; R² =H]

To 0.18 g (6 mmole) of 80% sodium hydride in 7.5 ml of drydimethylformamide was slowly added 0.9 g (6 mmole) of 4-t-butylphenol in2.5 ml of dimethylformamide. After cessation of hydrogen evolution, 1.3g (5 mmole) of solid 2-fluoro-5-nitrobenzanilide was added and the deepred solution was stirred at room temperature for 5 days. The reactionmixture was diluted with water and extracted with ethyl acetate. Theorganic layer was washed with IN hydrochloric acid, saturated aqueoussodium bicarbonate solution, dried with magnesium sulphate and thesolvent removed to yield the crude product. Recrystallisation frommethylene chloride and hexare yielded 0.92 g product (47%) m.p.138°-140° C.

EXAMPLE 5 2-phenoxy-5-nitrobenzanilide [R =Ph; R¹ =phenoxy; R² =H]

The procedure of Example 4 was followed giving a good yield of productwhich was characterised by its n.m.r. spectrum.

We claim:
 1. 2-(4-t-Octylphenoxy)-5-nitroacetanilide. 2.4-(4-t-Octylphenoxy)-3-nitroacetanilide. 3.2'-(2,4-di-t-pentylphenoxy)-5'-nitrobenzanilide.